US4719214A - Carbocyclic analogues of thymine nucleosides - Google Patents

Carbocyclic analogues of thymine nucleosides Download PDF

Info

Publication number
US4719214A
US4719214A US06/758,719 US75871985A US4719214A US 4719214 A US4719214 A US 4719214A US 75871985 A US75871985 A US 75871985A US 4719214 A US4719214 A US 4719214A
Authority
US
United States
Prior art keywords
formula
compound
group
carbocyclic
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/758,719
Inventor
Y. Fulmer Shealy
C. Allen O'Dell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SOUTHERN RESEARCH INSTITUTE A CORP OF ALABAMA
Southern Research Institute
Original Assignee
Southern Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Southern Research Institute filed Critical Southern Research Institute
Priority to US06/758,719 priority Critical patent/US4719214A/en
Assigned to SOUTHERN RESEARCH INSTITUTE, A CORP OF ALABAMA reassignment SOUTHERN RESEARCH INSTITUTE, A CORP OF ALABAMA ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: O'DELL, C. ALLEN, SHEALY, Y. FULMER
Application granted granted Critical
Publication of US4719214A publication Critical patent/US4719214A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • This invention relates to the preparation of carbocyclic analogues of thymine nucleosides, to the use of such compounds in the treatment of viral infections, and to certain novel compounds.
  • Thymidine is 5-methyl-2'-deoxyuridine. Therefore, carbocyclic analogues of thymine nucleosides are also carbocyclic analogues of 5-substituted-2'-deoxyuridines.
  • carbocyclic analogue of a nucleoside designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analogue; or, differently expressed, in the carbocyclic analogue a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside.
  • Such nucleoside analogues were designated carbocyclic analogues of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, Volume 88, pages 3885-3887, 1966.
  • the natural nucleosides and many of their true nucleoside analogues are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and purine or pyrimidine moieties.
  • enzymes phosphorylases and hydrolases
  • cleave the nucleosides to the pentose and purine or pyrimidine moieties For example, it has been reported by C. Desgranges et al. (Biochemical Pharmacology, Vol. 32, pages 3583-3590, 1983) that various 5-substituted-2'-deoxyuridines including 5-ethyl-2'-deoxyuridine (EDU) and 5-[(E)-2-(bromovinyl)]-2'-deoxyuridine (BVDU) are substrates for thymidine phosphorylase isolated from human blood platelets.
  • EEU 5-ethyl-2'-deoxyuridine
  • BVDU 5-[(E)-2
  • 4,396,623 to Shealy et al discloses a method for the treatment of viral infections by treating a host animal with a pharmaceutically effective amount of a carbocyclic analogue of a nucleoside represented by the formula: ##STR2## wherein X is chlorine, bromine, iodine, a lower alkyl group or an amino group of the formula --NHR 2 wherein R 2 is a lower alkyl group; and R and R 1 can be the same or different members selected from the group consisting of hydrogen, an alkanoyl group or an aroyl group.
  • R is a group having the formula --C.tbd.CSi(CH 3 ) 3 , --C.tbd.CH, --CH ⁇ CH 2 , --CH 2 CH 2 Si(CH 3 ) 3 or --CH 2 X;
  • X is a bromo, chloro or iodo;
  • R' is hydrogen or an acyl group, preferably one having from 2-7 carbon atoms, with the proviso that when R is --CH 2 X, R' is an acyl group.
  • Carbocyclic analogues of 5-substituted-2'-deoxyuridines represented by Formula I ##STR4## may be obtained by synthesis routes that begin with the carbocyclic analogue of 2'-deoxyuridine, which is represented by Formula 1. (All Arabic formula numbers refer to the formulas shown in the Charts A and B.) Examples of such routes are outlined in Chart A. In these routes, a 5-halo-2'-deoxyuridine analogue (Formula 4) is prepared as described by Shealy et al. in U.S. Pat. No. 4,396,623 and in the Journal of Medicinal Chemistry, Volume 26, pages 156-161 (1983) or as described in Example 2 herein.
  • Partial reduction of the 5-ethynyl derivative (Formula 6) by hydrogenation over a less active catalyst, such as the Lindlar catalyst, produces the 5-ethenyl derivative (Formula I, R --CH ⁇ CH 2 ) which can be further reduced to C-EDU.
  • a less active catalyst such as the Lindlar catalyst
  • Carbocyclic analogues of 5-substituted 2'-deoxyuridines represented by Formula I may be obtained also by synthesis routes that begin with the carbocyclic analogue of thymidine, which is represented in Chart B by Formula 9.
  • Such a replaceable group may be a halogen such as chlorine, bromine, or iodine.
  • the replaceable group is then replaced by an alkyl, an alkenyl, an alkynyl, or an aralkyl group. Replacement of the replaceable group may be effected by means of an alkyl, alkenyl, alkynyl, or aralkyl organometallic reagent.
  • a tribenzoyl derivative of the carbocyclic analogue (Formula 9) of thymidine is prepared by treating this carbocyclic analogue with benzoyl chloride in pyridine.
  • Diacyl derivatives represented by Formula 12 are converted to the carbocyclic analogue (Formula 13), such as C-EDU, by standard procedures, such as the use of basic media.
  • Example 14 the selective antiviral activities (VR) of C-EDU versus type 1 herpes simplex virus (HSV-1) and type 2 herpes simplex virus (HSV-2) are comparable to those of 9- ⁇ -D-arabinofuranosyladenine (Ara-A), a prescription antiviral drug.
  • C-EDU is as active vs. HSV-1 as is the corresponding true nucleoside, 5-ethyl-2'-deoxyuridine (EDU), which is also a clinically active drug.
  • C-EDU also has definite and significant activity against HSV-2.
  • C-EDU is not subject to the degradative actions of phosphorylases and hydrolases because it is a 1-cycloalkyl-2,4(1H,3H)-pyrimidinedione.
  • peaks listed are those arising from the molecular ion (M), those attributable to the loss of certain fragments (M minus a fragment), and some other prominent peaks. Fragments containing the complete pyrimidine moiety may be designated P plus an atom or group.
  • Method B The compound of this Example was also prepared by a new method comprised of the treatment of the compound of Example 1 with iodine monochloride. This method is illustrated by the following procedure.
  • the reaction mixture was concentrated to dryness in vacuo; the dark, solid residue was dissolved in chloroform (100 mL), and the chloroform solution was washed twice with 50-mL portions of a 10% aqueous solution of the disodium salt of ethylenediaminetetraacetic acid and twice with 50-mL portions of water.
  • the resulting chloroform solution was dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue.
  • the desired product was isolated by chromatography of the crude product on a column of silica gel 60 (50 g) with 9:1 chloroform-methanol as developing and eluting solvent.
  • the amorphous residue was triturated with 9:1 chloroform-methanol, the solvents were evaporated in vacuo, the solid residue was dissolved in a mixture of ethanol (3 mL) and ether (10 mL), the mixture (containing a small amount of a curdy precipitate) was refrigerated and then filtered, and the filtrate was concentrated in vacuo to a gummy residue.
  • Procedure A A mixture of the 5-ethynylpyrimidine (50 mg) of Example 4, a hydrogenation catalyst (60 mg of commercial 5% palladium-on-calcium carbonate containing lead), quinoline (0.2 mL), and acetone (10 mL) was treated with hydrogen at approximately atmospheric pressure. After 20 min. of stirring in the hydrogen atmosphere, the mixture was filtered to remove the catalyst, and the filtrate (including ethanol washings of the catalyst) was concentrated to dryness in vacuo. The crude product was purified by chromatography on a column of silica gel 60 (15 g) with 9:1 chloroform-methanol as the developing and eluting solvent.
  • Procedure B A suspension of the 5-ethynylpyrimidine (100 mg) of Example 4 and 5% palladium-on-charcoal catalyst in ethanol (10 mL) was treated with hydrogen at approximately atmospheric pressure. After 1 hr. in the hydrogen atmosphere, the mixture was filtered to remove the catalyst, and the filtrate (including ethanol washings of the catalyst) was concentrated to a residue that crystalized when it was triturated with ether. The white crystals were collected by filtration, washed with ether, and dried in vacuo at 56° C.: yield, 90% (92 mg.). The IR and 1 H-NMR spectra of this material showed that it was crude C-EDU.
  • the crystalline product was collected by filtration, washed with the same solvent, and dried in vacuo at 78° C.: yield, 68 mg (50%); mp 154°-156° C. (inserted at 100° C., 3° C./min.); TLC, 1 spot (5:1 chloroform-methanol); MS (FAB), m/e 327 (M+1), 311 (M-CH 3 ), 213 (P+2H), 197.
  • This material was purified by chromatography on a column of silica gel 60 (150 g) with 9:1 chloroform-methanol as the developing and eluting solution.
  • This material was soluble in ethanol and in ethyl acetate, but not in ether. When cyclohexane was added to an ethyl acetate solution of the glassy product, an amorphous precipitate formed. The solvents were evaporated under reduced pressure, and the white glass was kept in vacuo at 56° C.
  • a solution consisting of 1.15 g of the tribenzoyl derivative of Example 8, 133 mL of ethanol, 60 mL of water, and 7.2 mL of 1N hydrochloric acid was heated under gentle reflux for 24 hrs.
  • the reaction solution was concentrated to remove ethanol, and the aqueous mixture (containing a colorless syrup) was extracted twice with 50-mL portions of chloroform.
  • the total chloroform extract was washed with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a colorless gum.
  • a solution of the lithium dimethylcopper reagent was then prepared as follows.
  • a suspension of cuprous iodide (1.43 g) in dry ether (25 mL) was prepared under an argon atmosphere and was cooled to -15° C.
  • To this stirred suspension was added dropwise (during approximately 10 min.) a 1.5M solution (10 mL) of methyllithium in ether. A yellow precipitate formed initially, but the reaction mixture later became clear.
  • the desired product (C-EDU dibenzoate) was isolated by chromatography on silica gel 60 with 1:1 ethyl acetate-benzene as the developing and eluting solvent. The collection of fractions was monitored by TLC; fractions containing C-EDU dibenzoate were combined and concentrated in vacuo to a white solid foam: yield, 40% (120 mg.); mass spectrum (FAB), m/e 463 (M+1), 341 (M-C 6 H 5 COO).
  • Virus rating is a weighted measurement of antiviral activity determined by the method of Ehrlich et al., Annals of the New York Academy of Science, volume 130, pages 5-16, 1965. In tests carried out by this method, a VR of 0.5-0.9 indicates marginal to moderate antiviral activity, and a VR equal to or greater than 1 indicates definite antiviral activity. The higher the value of VR, the greater is the antiviral activity.
  • the MIC 50 minimum inhibitory concentration, 50% is the concentration of a test compound required for 50% inhibition of virus-induced cytopathogenic effects.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

There are disclosed compounds having the formula: ##STR1## wherein R is a group having the formula --C.tbd.CSi(CH3)3, --C.tbd.CH, --CH═CH2, --CH2 CH2 Si(CH3)3 or --CH2 X; X is bromo, chloro or iodo; and R' is hydrogen or an acyl group, with the proviso that when R is --CH2 X, R' is an acyl group. Certain of these compounds are active in inhibiting the replication of DNA viruses. Other of these compounds are useful as intermediates in the production of compounds which are active in inhibiting the replication of DNA viruses.

Description

BACKGROUND OF THE INVENTION
This invention relates to the preparation of carbocyclic analogues of thymine nucleosides, to the use of such compounds in the treatment of viral infections, and to certain novel compounds.
Thymidine is 5-methyl-2'-deoxyuridine. Therefore, carbocyclic analogues of thymine nucleosides are also carbocyclic analogues of 5-substituted-2'-deoxyuridines.
The term "carbocyclic analogue of a nucleoside" designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analogue; or, differently expressed, in the carbocyclic analogue a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside. Such nucleoside analogues were designated carbocyclic analogues of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, Volume 88, pages 3885-3887, 1966. The natural nucleosides and many of their true nucleoside analogues are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and purine or pyrimidine moieties. For example, it has been reported by C. Desgranges et al. (Biochemical Pharmacology, Vol. 32, pages 3583-3590, 1983) that various 5-substituted-2'-deoxyuridines including 5-ethyl-2'-deoxyuridine (EDU) and 5-[(E)-2-(bromovinyl)]-2'-deoxyuridine (BVDU) are substrates for thymidine phosphorylase isolated from human blood platelets. Furthermore, R. Kaul, K. Keppeler, G. Kiefer, and B. Hempel (Chemosphere, Vol. 11, pages 539-540, 1982) reported the identification of the cleavage products 5-ethyluracil and 5-(2-hydroxyethyl)uracil as metabolites of EDU in rats. The biological effects of such true nucleoside analogues may be lessened by the action of these degradative enzymes. In contrast, carbocyclic analogues of nucleosides do not possess the glycosidic bond present in the true nucleosides and, therefore, are not subject to the action of these degradative enzymes. They may also be more selective in their biological actions.
The synthesis of the carbocyclic analogue (Formula I, R═CH3) of thymidine was first reported by Y. F. Shealy and C. A. O'Dell in the Journal of Heterocyclic Chemistry, Volume 13, pages 1041-1047 (1976). Additional properties of the carbocyclic analogue of thymidine and the synthesis and properties of two related carbocyclic analogues of thymine nucleosides were reported by Shealy, O'Dell, and Thorpe in the Journal of Heterocyclic Chemistry, Volume 18, pages 383-389 (1981). In this latter article in the Journal of Heterocyclic Chemistry and in an article by Shealy, O'Dell, Thorpe and Coburn, Jr., in the Journal of Heterocyclic Chemistry, Volume 20, pages 655-661 (1983), it was shown that a claim [K. C. Murdock and R. B. Angier, Journal of the American Chemical Society, Volume 84, pages 3758-3764 (1962)] that the carbocyclic analogue of thymidine had been synthesized earlier was erroneous.
Antiviral activity by the carbocyclic analogue of thymidine and by other 5-substituted-2'-deoxyribofuranosides was disclosed by Shealy et al. in an article in the Journal of Medicinal Chemistry, Volume 26, pages 156-161 (1983). U.S. Pat. No. 4,396,623 to Shealy et al discloses a method for the treatment of viral infections by treating a host animal with a pharmaceutically effective amount of a carbocyclic analogue of a nucleoside represented by the formula: ##STR2## wherein X is chlorine, bromine, iodine, a lower alkyl group or an amino group of the formula --NHR2 wherein R2 is a lower alkyl group; and R and R1 can be the same or different members selected from the group consisting of hydrogen, an alkanoyl group or an aroyl group.
SUMMARY OF THE INVENTION
In accordance with this invention, there are provided compounds having the formula: ##STR3## wherein R is a group having the formula --C.tbd.CSi(CH3)3, --C.tbd.CH, --CH═CH2, --CH2 CH2 Si(CH3)3 or --CH2 X; X is a bromo, chloro or iodo; and R' is hydrogen or an acyl group, preferably one having from 2-7 carbon atoms, with the proviso that when R is --CH2 X, R' is an acyl group. Certain of these compounds are active in inhibiting the replication of DNA viruses. Other of these compounds are useful as intermediates in the production of compounds which are active in inhibiting the replication of DNA viruses.
DETAILED DESCRIPTION OF THE INVENTION
Carbocyclic analogues of 5-substituted-2'-deoxyuridines represented by Formula I ##STR4## may be obtained by synthesis routes that begin with the carbocyclic analogue of 2'-deoxyuridine, which is represented by Formula 1. (All Arabic formula numbers refer to the formulas shown in the Charts A and B.) Examples of such routes are outlined in Chart A. In these routes, a 5-halo-2'-deoxyuridine analogue (Formula 4) is prepared as described by Shealy et al. in U.S. Pat. No. 4,396,623 and in the Journal of Medicinal Chemistry, Volume 26, pages 156-161 (1983) or as described in Example 2 herein. From 5-halo-2'-deoxyuridine analogues, 5-ethynyl derivatives, such as the 5-(trimethylsilylethynyl) derivative (Formula 5), may be prepared. Conversion of the 5-(trimethylsilylethynyl) derivative to the carbocyclic analogue (Formula 6, R=H) of 5-ethynyl-2'-deoxyuridine may be effected in basic media. The carbocyclic analogue (C-EDU; Formula 8 with R=H) of 5-ethyl-2'-deoxyuridine is obtained by reduction of the 5-ethynyl derivative (Formula 6, R=H) by catalytic hydrogenation. Furthermore, the trimethylsilyl derivatives of C-EDU (Formula 7 with R=H or acetyl) are obtained following catalytic hydrogenation of the trimethylsilylethynyl derivative (Formula 5 with R=acetyl). Partial reduction of the 5-ethynyl derivative (Formula 6) by hydrogenation over a less active catalyst, such as the Lindlar catalyst, produces the 5-ethenyl derivative (Formula I, R=--CH═CH2) which can be further reduced to C-EDU. ##STR5##
Carbocyclic analogues of 5-substituted 2'-deoxyuridines represented by Formula I may be obtained also by synthesis routes that begin with the carbocyclic analogue of thymidine, which is represented in Chart B by Formula 9. In these routes, a replaceable substituent is introduced into the methyl group of the carbocyclic analogue (Formula 9) of thymidine or a deriviative thereof (for example, Formulas 10 and 11 with X=H). Such a replaceable group may be a halogen such as chlorine, bromine, or iodine. The replaceable group is then replaced by an alkyl, an alkenyl, an alkynyl, or an aralkyl group. Replacement of the replaceable group may be effected by means of an alkyl, alkenyl, alkynyl, or aralkyl organometallic reagent.
The synthesis routes of Chart B are illustrated as follows. A tribenzoyl derivative of the carbocyclic analogue (Formula 9) of thymidine is prepared by treating this carbocyclic analogue with benzoyl chloride in pyridine. The tribenzoyl derivative, which is represented by Formula 10 wherein X=H and R'=phenyl, is then converted in weakly acidic media to a dibenzoyl derivative (Formula 11 with X=H and R'=phenyl) of the carbocyclic analogue of thymidine. The introduction of a bromo substituent on the methyl group of the dibenzoyl derivative, or of a similar diacyl derivative such as the analogous diacetyl derivative, produces the desired 5-(bromomethyl)-2'-deoxyuridine analogue (Formula 11 with X=Br). The obtention of a diacyl 5-substituted-2'-deoxyuridine analogue represented by Formula 12 is effected by treating the 5-(bromomethyl) derivative (Formula 11) with an organometallic reagent such as lithium dimethylcopper, i.e. (CH3)2 CuLi. Diacyl derivatives represented by Formula 12 are converted to the carbocyclic analogue (Formula 13), such as C-EDU, by standard procedures, such as the use of basic media. Alternatively, the tribenzoyl 5-(bromomethyl) derivative represented by Formula 10 with X=Br may be treated with an organometallic reagent to introduce the desired alkyl, alkenyl, alkynyl, or aralkyl substituent; the benzoyl groups may then be removed in basic media in order to obtain the desired 5-substituted 2'-deoxyuridine analogue represented by Formula 13.
As shown in Table 1, Example 14, the selective antiviral activities (VR) of C-EDU versus type 1 herpes simplex virus (HSV-1) and type 2 herpes simplex virus (HSV-2) are comparable to those of 9-β-D-arabinofuranosyladenine (Ara-A), a prescription antiviral drug. Furthermore, C-EDU is as active vs. HSV-1 as is the corresponding true nucleoside, 5-ethyl-2'-deoxyuridine (EDU), which is also a clinically active drug. C-EDU also has definite and significant activity against HSV-2. However, unlike EDU, which possesses a glycosidic bond that can undergo enzymatic scission to 5-ethyluracil or a derivative thereof (e.g., as reported by Kaul, Keppeler, Kiefer, and Hempel, loc. cit.), C-EDU is not subject to the degradative actions of phosphorylases and hydrolases because it is a 1-cycloalkyl-2,4(1H,3H)-pyrimidinedione. The carbocyclic analogue (Formula6 with R=H, Example 4) of 5-ethynyl-2'-deoxyuridine also has significant antiviral activity vs. both HSV-1 and HSV-2. The carbocyclic analogue (Formula 7 with R=H, Example 7) of 5-trimethylsilylethyl-2'-deoxyuridine also has antiviral activity vs. HSV-1.
Compounds prepared in accordance with this invention are illustrated by, but are not limited to, the following examples. The system of designating the orientation of substituents on the cyclopentane ring as α or β is that used by Chemical Abstracts, beginning with Volume 76, in the Chemical Substance Index. In the examples illustrating syntheses of the compounds of this invention, data were acquired and are reported as follows. Decomposition and melting temperatures (mp) were determined in capillary tubes. Ultraviolet spectra (UV) were recorded with a recording spectrophotometer and absorption maxima are reported in nanometers; sh=shoulder. Solutions for ultraviolet spectral determinations were prepared by diluting a 5-mL aliquot of a water or ethanol solution to 50 mL with 0.1N hydrochloric acid, phosphate buffer (pH 7), or 0.1N sodium hydroxide. Absorption maxima of these solutions are reported as being determined at pH 1, 7, or 13, respectively. Infrared spectra (IR) were recorded from samples in pressed potassium bromide discs; s=strong, vs=very strong, sh=shoulder, w=weak. Mass spectral data (MS) were taken from low-resolution, electron-impact spectra determined at 70 eV or from spectra determined by the fast-atom-bombardment (FAB) method. The peaks listed are those arising from the molecular ion (M), those attributable to the loss of certain fragments (M minus a fragment), and some other prominent peaks. Fragments containing the complete pyrimidine moiety may be designated P plus an atom or group. Nuclear magnetic resonance spectra were determined at 300.64 MHz for proton (1 H NMR) spectra. The internal standard was tetramethylsilane; s=singlet, t=triplet, q=quartet, qn=quintet, m=multiplet. Thin-layer chromatography (TLC) was performed on plates of silica gel, the developing solvent is specified parenthetically, and developed plates were examined by ultraviolet light.
EXAMPLE 1 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-2,4-(1H,3H)-pyrimidinedione Diacetate (Formula 2, R=CH3 CO--)
A solution (protected from atmospheric moisture) of 0.63 mL of acetic anhydride, 10 mL of anhydrous pyridine, and 0.5 g of the carbocyclic analogue (Formula 1) of 2'-deoxyuridine was stirred at room temperature for 21 hr. The reaction solution was then concentrated under reduced pressure by means of a vacuum (oil) pump. The residue was mixed well with water (2 mL), the mixture was concentrated in vacuo, the solid residue was triturated with ethyl acetate (5 mL), and this mixture was placed in a refrigerator. The white crystalline solid was separated by filtration, washed with ethyl acetate, and dried in vacuo at 56° C.: yield, 476 mg (70%); mp 110°-112° C.; TLC, 1 spot (9:1 chloroform-methanol); MS (electron-impact, direct-probe temperature 20° C.), m/e 310 (M), 250 (M-CH3 COOH), 207, 189, 177, 147, 139 (P+C2 H4), 134, 113, (P+2H), 112 (P+H), 96.
Analysis. Calcd. for C14 H18 N2 O6 : C, 54.19; H, 5.85; N, 9.03. Found: C, 53.85; H, 5.69; N, 8.89.
EXAMPLE 2 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-iodo-2,4(1H,3H)-pyrimidinedione Diacetate (Formula 4, X=I, R=CH3 CO--)
Method A. As revealed in U.S. Pat. No. 4,396,623, Aug. 2, 1983, the carbocyclic analogue of 5-iodo-2'-deoxyuridine (Formula 3, X=I) was prepared by treating the carbocyclic analogue (Formula 1) of 2'-deoxyuridine with iodine and nitric acid. The compound represented by Formula 4 with X=I and R=acetyl was prepared, as revealed in the aforementioned U.S. Pat. No. 4,396,623, by treating the carbocyclic analogue of 5-iodo-2'-deoxyuridine with acetic anhydride in pyridine.
Method B. The compound of this Example was also prepared by a new method comprised of the treatment of the compound of Example 1 with iodine monochloride. This method is illustrated by the following procedure.
A solution (protected from atmospheric moisture) of dichloromethane (17 mL), iodine monochloride (0.1 mL), and the compound (460 mg.) of Example 1 (Formula 2, R=acetyl) was boiled under reflux for 3 hr. The reaction solution was cooled to room temperature and diluted with water (14 mL), and an aqueous solution of sodium hydrogen sulfite (2%) was added dropwise to the vigorously stirred solution until its purple color disappeared. Dichloromethane was evaporated under reduced pressure from the solution, and the resulting mixture, containing a white precipitate, was placed in a refrigerator overnight. The white solid precipitate was collected by filtration, washed well with cold water, and dried in vacuo at 56° C.: yield, 580 mg. (89.6%); mp 176°-178° C. This material was recrystallized from methanol: weight of recrystallized product, 530 mg (91% recovery); mp 180°-184° C.
EXAMPLE 3 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-(trimethylsilylethynyl)-2,4(1H,3H )-pyrimidinedione Diacetate (Formula 5, R=CH3 CO--)
A suspension of 750 mg of the carbocyclic analogue (Formula 4 with X=I and R=acetyl) of 5-iodo-2'-deoxyuridine diacetate in triethylamine (75 mL) was vigorously deoxygenated by bubbling argon through the mixture. To this mixture, under an atmosphere of argon, was added (trimethylsilyl)acetylene (0.75 mL), bis(triphenylphosphine)palladium(II) chloride (25 mg), and cuprous iodide (25 mg), and the resulting mixture was stirred under argon at 50° C. for 3 hr. The reaction mixture was concentrated to dryness in vacuo; the dark, solid residue was dissolved in chloroform (100 mL), and the chloroform solution was washed twice with 50-mL portions of a 10% aqueous solution of the disodium salt of ethylenediaminetetraacetic acid and twice with 50-mL portions of water. The resulting chloroform solution was dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue. The desired product was isolated by chromatography of the crude product on a column of silica gel 60 (50 g) with 9:1 chloroform-methanol as developing and eluting solvent. Fractions that were shown by TLC to contain the desired product were combined and concentrated in vacuo to a pale buff-colored solid; weight, 640 mg (91.8%) yield. A hot solution of this material in ethyl acetate was diluted with cyclohexane (12 mL), and the resulting solution was allowed to cool to room temperature and then placed in a refrigerator overnight. A white crystalline precipitate was collected by filtration, washed with cold cyclohexane, and dried in vacuo; yield, 525 mg (75%); mp 181°-184° C., UV max 298 nm (ε 14600) and 237 (ε 12200) at pH 1, 297 nm (ε 14800) and 236 (ε 12400) at pH 7, 288 nm (ε 9900) and 232 (ε 12200) at pH 13; MS (electron-impact, direct-probe temperature 20° C.), m/e 406 (M), 391 (M-CH3), 346 (M-CH3 COOH), 331, 309, 289, 273, 271, 235 (P+C2 H4), 208 (P+H), 199 (M-P), 193; IR (2200-1200 cm-1 region) 2155 (--C.tbd.C--), 1740 vs, 1725 s, 1680 vs, 1610, 1470, 1460 w, 1450 w, 1435, 1405, 1380, 1365, 1350 sh, 1340 sh, 1315, 1305, 1290, 1265 vs, 1255 sh, 1240, 1230; medium-strong IR bands at 1040, 890 and 845 cm-1.
Analysis. Calcd. for C19 H26 N2 O6 Si: C, 56.13; H, 6.45; N, 6.89. Found: C, 56.06; H, 6.78; N, 6.95.
EXAMPLE 4 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-ethynyl-2,4(1H,3H)-pyrimidinedione (Formula 6, R=H)
A solution of 375 mg of the (trimethylsilyl)ethynyl derivative of Example 3 in 15 mL of a 0.2M solution of sodium methoxide in methanol was stirred under an argon atmosphere overnight at room temperature. The solution was diluted with water, and the proton form of a cation-exchange resin (previously washed with methanol) was added to the stirred mixture until the solution was approximately neutral (about pH 6). The resin was removed by filtration, the filtrate (combined with copious methanol washings of the residue) was treated with activated charcoal, and the resulting filtrate (plus methanol washings) was concentrated in vacuo. The amorphous residue was triturated with 9:1 chloroform-methanol, the solvents were evaporated in vacuo, the solid residue was dissolved in a mixture of ethanol (3 mL) and ether (10 mL), the mixture (containing a small amount of a curdy precipitate) was refrigerated and then filtered, and the filtrate was concentrated in vacuo to a gummy residue. The residue was triturated with ethyl acetate (4 mL) to induce crystallization, and the crystalline solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at 56° C.: yield, 140 mg (61%); mp 190°-193° C.; MS (electron impact, direct-probe temperature 20° C.), m/e 250 (M), 206, 169, 163 (P+C2 H4), 155, 137, (P+2H), 135 (P+H); UV max 292 nm (ε 11900) and 230 (ε 10100) at pH 1, 292 nm (ε 12000) and 230 (ε 10200) at zH 7, 288 nm (ε 9600) and 231 (ε 11300) at pH 13.
Analysis. Calcd. for C12 H14 N2 O4.0.1H2 O: C, 57.18; H, 5.68; N, 11.12. Found: C, 56.91; H, 5.86; N, 10.82.
EXAMPLE 5 5-Ethyl-1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-2,4(1H,3H)-pyrimidinedione (The Carbocyclic Analogue of 5-Ethyl-2'-deoxyuridine, C-EDU, Formula 8, R=H) From the 5-Ethynyl Derivative of Example 4
Procedure A. A mixture of the 5-ethynylpyrimidine (50 mg) of Example 4, a hydrogenation catalyst (60 mg of commercial 5% palladium-on-calcium carbonate containing lead), quinoline (0.2 mL), and acetone (10 mL) was treated with hydrogen at approximately atmospheric pressure. After 20 min. of stirring in the hydrogen atmosphere, the mixture was filtered to remove the catalyst, and the filtrate (including ethanol washings of the catalyst) was concentrated to dryness in vacuo. The crude product was purified by chromatography on a column of silica gel 60 (15 g) with 9:1 chloroform-methanol as the developing and eluting solvent. Effluent fractions that were shown by means of a recording UV monitor to contain the desired product were combined and concentrated to dryness. The residue was triturated with ethyl acetate (2 mL), and the white crystalline product (C-EDU) was collected by filtration, washed with ethyl acetate, and dried in vacuo at 56° C.: yield, 63% (32 mg); mp 148°-151° C. (capillary inserted at 45° C., heating rate 3° C./min.); TLC, 1 spot (5:1 chloroform-methanol); UV max 274 nm (ε 10300) at pH 1, 273 (ε 10500) at pH 7, and 271 (ε 8000) at pH 13; MS (electron-impact, direct-probe temperature 200° C.), m/e 254 (M), 239 (M-CH3), 224 (M-CH2 OH+H), 195 (M-CO-CH2 OH), 167 (P+C2 H4), 141 (P+2H), 140 (P+H); IR (1800-1300 cm-1 region) 1685 vs, 1670 vs, 1640, 1515 w, 1475, 1465, 1435 w, 1420, 1390, 1370, 1335, 1315; 1 H-NMR (Me2 SO-d6) δ1.02 t (CH3), 1.42 m and 2.05 m (CH2, position 5 of the cyclopentyl group), 1.7-2.0 m (CH2 position 2 of the cyclopentyl group), 1.91 m (CH, position 4 of the cyclopentyl group), 2.22 q (CH2 of the ethyl group), 3.45 m (CH2 of CH2 OH), 3.98 m (CHOH, position 3 of the cyclopentyl group), 4.60 t (HO of CH2 OH), 4.70 d (HO at position 3 of the cyclopentyl group), 4.96 m (CH, position 1 of the cyclopentyl group), 7.47 s (CH, position 6 of the pyrimidine ring), 11.16 s (NH of pyrimidine ring).
Analysis. Calcd. for C12 H18 N2 O4 : C, 56.68; H, 7.14; N, 11.02. Found: C, 56.30; H, 7.16; N, 10.97.
Procedure B. A suspension of the 5-ethynylpyrimidine (100 mg) of Example 4 and 5% palladium-on-charcoal catalyst in ethanol (10 mL) was treated with hydrogen at approximately atmospheric pressure. After 1 hr. in the hydrogen atmosphere, the mixture was filtered to remove the catalyst, and the filtrate (including ethanol washings of the catalyst) was concentrated to a residue that crystalized when it was triturated with ether. The white crystals were collected by filtration, washed with ether, and dried in vacuo at 56° C.: yield, 90% (92 mg.). The IR and 1 H-NMR spectra of this material showed that it was crude C-EDU.
EXAMPLE 6 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-[2-(trimethylsilyl)ethyl]-2,4(1H,3H)-pyrimidinedione Diacetate (Formula 7, R=Acetyl)
A mixture of the 5-(trimethylsilylethynyl)pyrimidine (173 mg) of Example 3, ethanol (20 mL), and 5% palladium-on-charcoal (100 mg) was stirred for 45 min. in an atmosphere of hydrogen at approximately atmospheric pressure. The mixture was filtered to remove the catalyst, and the filtrate (including ethanol washings of the catalyst) was concentrated in vacuo to a colorless syrup: yield, 173 mg (99%). The mass spectrum (FAB) of this material showed that it was the compound represented by Formula 7 with R=CH3 CO: m/e 411 (M+1), 395 (M-CH3), 351 (395-CH3 CO-H), 213 (P+2H), 197.
EXAMPLE 7 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-[2-(trimethylsilyl)ethyl]-2,4(1H,3H)-pyrimidinedione (Formula 7, R=H)
A solution of the diacetate (170 mg) of Example 6 in ammonia-methanol (17 mL, 10% ammonia) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to a syrupy residue. The desired product (Formula 7 with R=H) was isolated by chromatography on silica gel with 5:1 chloroform-methanol as the developing and eluting solvent. The collection of fractions was monitored by TLC; fractions containing the desired product were combined and concentrated under reduced pressure. Further concentration in vacuo with a vacuum pump left a crystalline residue that was triturated with 1:1 ethyl acetate-cyclohexane (3 mL). The crystalline product was collected by filtration, washed with the same solvent, and dried in vacuo at 78° C.: yield, 68 mg (50%); mp 154°-156° C. (inserted at 100° C., 3° C./min.); TLC, 1 spot (5:1 chloroform-methanol); MS (FAB), m/e 327 (M+1), 311 (M-CH3), 213 (P+2H), 197.
Analysis. Calcd. for C15 H26 N2 O4 Si: C, 55.18; H, 8.03; N, 8.58. Found: C, 55.16; H, 8.01; N, 8.46.
EXAMPLE 8 Tribenzoyl Derivative of the Carbocyclic Analogue of Thymidine (Formula 10 with X=H and R'=Phenyl)
A solution consisting of 5.0 mL of benzoyl chloride, 2.0 g of the carbocyclic analogue (Formula 9) of thymidine; and 100 mL of dry pyridine was heated at 57°-58° C. for 70 hr. The reaction solution was added slowly to a water-ice mixture (800 mL), and the amorphous precipitate that formed was extracted into chloroform (total, 300 mL). The chloroform solution was washed successively with three 100-mL portions of 0.1N hydrochloric acid, saturated sodium bicarbonate solution, and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to a yellow gum (weight 4.3 g). This material was purified by chromatography on a column of silica gel 60 (150 g) with 9:1 chloroform-methanol as the developing and eluting solution. The fractions that contained the tribenzoyl derivative (Formula 10 with X=H and R'=phenyl) were selected by TLC and were combined and concentrated in vacuo to a white glass; yield, 4.02 g (88%). This material was soluble in ethanol and in ethyl acetate, but not in ether. When cyclohexane was added to an ethyl acetate solution of the glassy product, an amorphous precipitate formed. The solvents were evaporated under reduced pressure, and the white glass was kept in vacuo at 56° C. for 3 hr. and then submitted for analysis: MS (electron impact, direct-probe temperature 250° C.), m/e 552 (M), 524, 482, 447 (M-C6 H5 CO), 430 (M-C6 H5 COOH), 326, 325, 203, 126, 122 (C6 H5 COOH), 105 (C6 H5 CO); 1 H-NMR (CDCl3) δ1.77 m and 2.52 m (CH2, position 5 of the cyclopentyl group), 1.91 s (CH3), 2.37 m (CH2, position 2 of the cyclopentyl group), 2.75 m (CH, position 4 of the cyclopentyl group), 4.52 d (CH2 of --CH2 OCOC6 H5), 5.22 qn (CH , position 1 of the cyclopentyl group), 5.46 m (CH, position 3 of the cyclopentyl group), 7.15 s (CH, position 6 of the pyrimidinyl group), 7.32-7.67 m (CH, positions 3, 4, and 5 of the phenyl groups), 7.86-8.06 m (CH, positions 2 and 6 of the phenyl groups).
Analysis. Calcd. for C32 H28 N2 O7.0.5 ethyl acetate: C, 68.44; H, 5.41; N, 4.69. Found: C, 68.62; H, 5.18; N, 4.41.
EXAMPLE 9 Tribenzoyl Derivative of 5-(Bromomethyl)-1-[(1α,3β,4α)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-2,4(1H,3H)-pyrimidinedione (Formula 10 with X=Br and R'=Phenyl).
A mixture of the tribenzoyl derivative (1.26 g) of Example 8, N-bromosuccinimide (504 mg), and carbon tetrachloride (120 mL) was boiled under reflux for 1 hr. and simultaneously was exposed to light from a 150-Watt flood lamp that was 10 cm from the reaction flask. The hot solution was decanted from a tarry precipitate and was concentrated in vacuo and under anhydrous conditions to a glassy residue: weight, 1.43 g. The mass spectrum and the proton NMR spectrum showed that the product was predominantly the compound represented by Formula 10 with X=Br and R'=phenyl: MS (electron-impact, direct-probe temperature 250° C.), m/e 630 (M), 551 (M-Br), 323 (M-P); 1 H-NMR (CDCl3) δ1.83 m and 2.57 m (CH2, position 5 of the cyclopentyl group), 2.43 m (CH2, position 2 of the cyclopentyl group), 2.78 m (CH, position 4 of the cyclopentyl group), 4.24 s (CH2 Br), 4.56 d (CH2 OCOPh), 5.22 m (CH, position 1 of the cyclopentyl group), 5.49 m (CH, position 3 of the cyclopentyl group), 7.59 s (CH, position 6 of the pyrimidinyl group), 7.42 m and 7.51 m (positions 3 and 5 of the phenyl groups), 7.57 m and 7.66 m (position 4 of the phenyl groups), 7.92 m and 8.01 m (positions 2 and 6 of the phenyl groups).
EXAMPLE 10 1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-5-methyl-2,4(1H,3H)-pyrimidinedione Dibenzoate (Dibenzoyl Derivative of the Carbocyclic Analogue of Thymidine, Formula 11 with X=H and R'=Phenyl)
A solution consisting of 1.15 g of the tribenzoyl derivative of Example 8, 133 mL of ethanol, 60 mL of water, and 7.2 mL of 1N hydrochloric acid was heated under gentle reflux for 24 hrs. The reaction solution was concentrated to remove ethanol, and the aqueous mixture (containing a colorless syrup) was extracted twice with 50-mL portions of chloroform. The total chloroform extract was washed with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a colorless gum. The residue was mixed well with ethanol (15 mL); the mixture (containing white crystals) was stored in a freezer (-20° C.); and the crystalline product was collected by filtration, washed with cold ethanol, and dried in vacuo: yield, 725 mg (78%); mp 173°-176° C.; mass spectrum (FAB), m/e 449 (M+1), 327 (M-C6 H5 COO); 1 H-NMR (CDCl3) δ1.73 m and 2.50 m (CH2, position 5 of the cyclopentyl group), 1.89 s (CH3), 2.35 m (CH2, position 2 of the cyclopentyl group), 2.77 m (CH, position 4 of the cyclopentyl group), 4.54 d (CH2 OCOPh), 5.24 qn (CH, position 1 of the cyclopentyl group), 5.47 m (CH, position 3 of the cyclopentyl group), 7.06 s (CH, position 6 of the pyrimidinyl group), 7.42 m (CH, positions 3 and 5 of the phenyl groups), 7.56 m (CH, position 4 of the phenyl groups), 8.01 m (CH, positions 2 and 6 of the phenyl groups).
Analysis. Calcd. for C25 H24 N2 O6 : C, 66.95; H, 5.39; N, 6.25. Found: C, 66.67; H, 5.77; N, 6.41.
EXAMPLE 11 5-(Bromomethyl)-1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-2,4(1H,3H)-pyrimidinedione Dibenzoate (Formula 11 with X=Br and R'=C6 H5)
A mixture of N-bromosuccinimide (149 mg), 300 mg of the carbocyclic analogue (Formula 11 with X=H and R'=phenyl) of thymidine dibenzoate, and dry carbon tetrachloride (34 mL) was boiled under reflux for 1 hr. and simultaneously was exposed to light (provided by a 150-Watt flood lamp). The colorless solution was decanted from a waxy precipitate and was concentrated in vacuo under anhydrous conditions to a gummy residue; yield, 99% (350 mg). The mass spectrum and the 1 H-NMR spectrum of this material demonstrated that it was predominantly the desired 5-(bromomethyl)uracil derivative (Formula 11 with X=Br and R'=phenyl): MS (FAB), m/e 447 (M-Br), 405 (M-C6 H5 COO), 323 (M-P); 1 H-NMR (CDCl3) δ1.82 m and 2.55 m (CH2, position 5 of the cyclopentyl group), 2.41 s (CH2, position 2 of the cyclopentyl group), 2.8 m (CH, position 4 of the cyclopentyl group), 4.23 d (CH2 Br), 4.57 d (CH2 OCOPh), 5.21 qn (CH, position 1 of the cyclopentyl group), 5.52 m (CH, position 3 of the cyclopentyl group), 7.49 s (CH, position 6 of the pyrimidinyl group), 7.45 m (CH, positions 3 and 5 of the phenyl groups), 7.58 m (position 4 of the phenyl groups), 8.04 m (positions 2 and 6 of the phenyl groups).
EXAMPLE 12 5-Ethyl-1-[(1α,3β,4α)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl]-2,4(1H,3H)-pyrimidinedione Dibenzoate (C-EDU Dibenzoate, Formula 12 with R"=Methyl and R'=Phenyl)
A solution of the 5-bromomethyl)uracil derivative (350 mg) of Example 11 in a mixture of dry ether (10 mL) and dry tetrahydrofuran (5 mL) was prepared under an argon atmosphere and was cooled to -15° C. A solution of the lithium dimethylcopper reagent was then prepared as follows. A suspension of cuprous iodide (1.43 g) in dry ether (25 mL) was prepared under an argon atmosphere and was cooled to -15° C. To this stirred suspension was added dropwise (during approximately 10 min.) a 1.5M solution (10 mL) of methyllithium in ether. A yellow precipitate formed initially, but the reaction mixture later became clear. A portion (5.6 mL) of the solution of lithium dimethylcopper was added dropwise to the stirred, cold (-15° C.) solution of the 5-(bromomethyl)uracil derivative, and the resulting mixture was kept at 3° C. overnight. An aqueous solution of ammonium chloride (5%, 15 mL) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hr. and then extracted twice with chloroform (2×30 mL). The total chloroform extract was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a syrup. The desired product (C-EDU dibenzoate) was isolated by chromatography on silica gel 60 with 1:1 ethyl acetate-benzene as the developing and eluting solvent. The collection of fractions was monitored by TLC; fractions containing C-EDU dibenzoate were combined and concentrated in vacuo to a white solid foam: yield, 40% (120 mg.); mass spectrum (FAB), m/e 463 (M+1), 341 (M-C6 H5 COO).
EXAMPLE 13 5-Ethyl-1-[1α,3β,4α-3-hydroxy-(4-hydroxymethyl)cyclopentyl]-2,4(1H,3H)-pyrimidinedione (C-EDU, Formula 8 with R=H or Formula 13 with R"=CH3) From the Dibenzoyl Derivative of Example 12
A solution of 115 mg of the dibenzoyl derivative of C-EDU in an ammonia-methanol solution (10 mL, 10% ammonia) was stirred at room temperature for 2.5-3 days. The reaction solution was concentrated under reduced pressure to a syrupy residue. C-EDU was isolated by applying a methanol solution of the residue to a preparative TLC plate of silica gel and developing the chromatogram with 5:1 chloroform-methanol. The principal band was scraped from the plate and extracted in a Soxhlet extractor with hot ethanol for 2 hr. The ethanol extract was concentrated to dryness, a small amount of ethanol was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure to a colorless syrup. The residue was triturated with ethyl acetate, and the resulting white crystalline solid was collected by filtration, and dried in vacuo: yield, 41 mg (65%); mp 147°-150° C. (capillary inserted at 50° C., heating rate 3° C./min.); TLC, 1 spot (5:1 chloroform-methanol); MS (FAB), m/e 255 (M+1), 141 (P+2H). The melting point of a mixture of this material and the specimen described in Procedure A of Example 5 was 147°-150° C. (capillary inserted at 50° C., 3° C./min.). When this material and the specimen of C-EDU described in Example 5 were applied side-by-side on a TLC plate of silica gel, they moved side-by-side (Rf ca. 0.5) when the chromatogram was developed with 5:1 chloroform-methanol. Similarly, reverse-phase HPLC (μ Bondapak C18 column; solvent 90:10 0.01M aqueous ammonium dihydrogen phosphate-methanol, isocratic) of the two specimens monitored at 254 nm showed that their retention times (15.46 min. and 15.45 min.) were the same. The IR spectrum of the specimen obtained by the method described in this Example was identical with the IR spectrum of the specimen of C-EDU described in Example 5. Thus, the melting temperatures, TLC, HPLC, and the IR spectra show that the specimens of Example 5 and 13 are identical.
EXAMPLE 14 Antiviral Activity of Carbocyclic Analogues of Some Thymine Nucleosides
Carbocyclic analogues of thymine nucleosides were tested for antiviral activity against viruses that replicate in mammalian cells growing in cell culture. The results of these tests against herpes simplex viruses are summarized in Table 1. The Virus rating (VR) is a weighted measurement of antiviral activity determined by the method of Ehrlich et al., Annals of the New York Academy of Science, volume 130, pages 5-16, 1965. In tests carried out by this method, a VR of 0.5-0.9 indicates marginal to moderate antiviral activity, and a VR equal to or greater than 1 indicates definite antiviral activity. The higher the value of VR, the greater is the antiviral activity. The MIC50 (minimum inhibitory concentration, 50%) is the concentration of a test compound required for 50% inhibition of virus-induced cytopathogenic effects.
The results summarized in Table 1 demonstrate that the carbocyclic analogue (C-EDU, Formula 8 with R=H) of 5-ethyl-2'-deoxyuridine inhibits the replication of both type 1 herpes simplex virus (HSV-1) and type 2 herpes simplex virus (HSV-2). The results summarized in Table 1 also show that the carbocyclic analogue of 5-ethynyl-2'-deoxyuridine has significant, selective activity against both HSV-1 and HSV-2 and that the carbocyclic analogue of 5-trimethylsilylethyl-2'-deoxyuridine has activity against HSV-1.
                                  TABLE 1                                 
__________________________________________________________________________
Antiviral Activity of Carbocyclic                                         
Analogues of Thymine Nucleosides                                          
                    Herpes Simplex Virus                                  
                    Type 1, Strain 377                                    
                              Type 2, Strain MS                           
                         MIC.sub.50                                       
                                   MIC.sub.50                             
Compound      Host.sup.a Cells                                            
                    VR   mcg./ml.                                         
                              VR   mcg./ml.                               
__________________________________________________________________________
Carbocyclic analogue of                                                   
              Vero  0.9  253  1.1  207                                    
5-ethynyl-2'-deoxyuridine                                                 
(Formula 6 with R = H,                                                    
Example 4)                                                                
Carbocyclic analogue of                                                   
              Vero  0.5  320                                              
5-trimethylsilylethyl-                                                    
2'-deoxyuridine                                                           
(Formula 7 with R = H,                                                    
Example 7)                                                                
C-EDU (Formula 8 with                                                     
              Vero  2.4  45   1.1  227                                    
R = H, Examples 5 or 13)                                                  
                    2.1  69   1.1  178                                    
EDU.sup.b     Vero  2.3  19   2.2  321                                    
Ara-A.sup.b   Vero  2.0-2.1                                               
                         15-19                                            
                              1.3-1.7                                     
                                   22-45                                  
__________________________________________________________________________
 .sup.a Antiviral evaluations were performed with HSV1 or HSV2 replicating
 in Vero cells.                                                           
 .sup.b 9D-Arabinofuranosyladenine (AraA) and the true nucleoside         
 5ethyl-2deoxyuridine (EDU) were tested as positive controls.

Claims (15)

We claim:
1. A compound having the formula ##STR6## wherein R is a group having the formula --C.tbd.CSi(CH3)3, --C.tbd.CH, --CH═CH2, --CH2 CH2 Si(CH3)3 or --CH2 X; X is bromo, chloro or iodo; and
R' is hydrogen, an acetyl group or a benzoyl group, with the proviso that when R is --CH2 X, R' is an acetyl group or a benzoyl group.
2. A compound as defined in claim 1 wherein R is --C.tbd.CSi(CH3)3.
3. A compound as defined in claim 2 wherein R' is acetyl.
4. A compound as defined in claim 1 wherein R is --C.tbd.CH.
5. A compound as defined in claim 4 wherein R' is hydrogen.
6. A compound as defined in claim 1 wherein R is --CH2 CH2 Si(CH3)3.
7. A compound as defined in claim 6 wherein R' is acetyl.
8. A compound as defined in claim 6 wherein R' is hydrogen.
9. A compound as defined in claim 1 wherein R is --CH2 X and X is bromo, chloro or iodo.
10. A compound as defined in claim 9 wherein X is Br and R' is benzoyl.
11. A process for the treatment of a host animal having a herpes virus infection which comprises administering to said host animal a therapeutically effective amount of a compound as defined in claim 5.
12. A process for the treatment of a host animal having a herpes virus infection which comprises administering to said host animal a therapeutically effective amount of a compound as defined in claim 8.
13. A compound having the formula ##STR7## wherein X is hydrogen, bromo, chloro or iodo and R' is a phenyl group.
14. A compound as defined in claim 13 wherein X is hydrogen.
15. A compound as defined in claim 13 wherein X is bromo.
US06/758,719 1985-07-25 1985-07-25 Carbocyclic analogues of thymine nucleosides Expired - Lifetime US4719214A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US06/758,719 US4719214A (en) 1985-07-25 1985-07-25 Carbocyclic analogues of thymine nucleosides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/758,719 US4719214A (en) 1985-07-25 1985-07-25 Carbocyclic analogues of thymine nucleosides

Publications (1)

Publication Number Publication Date
US4719214A true US4719214A (en) 1988-01-12

Family

ID=25052817

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/758,719 Expired - Lifetime US4719214A (en) 1985-07-25 1985-07-25 Carbocyclic analogues of thymine nucleosides

Country Status (1)

Country Link
US (1) US4719214A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990009177A1 (en) * 1989-01-31 1990-08-23 Us Army Cyclopentenyl pyrimidines and methods of using same
WO1991015488A1 (en) * 1990-04-04 1991-10-17 Froud, Clive Carbo-nucleoside derivatives
WO1992004901A1 (en) * 1990-09-26 1992-04-02 The Wellcome Foundation Limited Uracil reductase inactivators
US5496935A (en) * 1988-08-17 1996-03-05 Max-Delbru/ ck-Centrum 2',3'-dideoxynucleoside pyrimidine compounds and carbocyclic analogs
EP0711555A2 (en) * 1990-07-19 1996-05-15 The Wellcome Foundation Limited Enzyme inactivators
US5744600A (en) * 1988-11-14 1998-04-28 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Phosphonomethoxy carbocyclic nucleosides and nucleotides

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2084152A (en) * 1980-10-01 1982-04-07 Beecham Group Ltd Antiviral agents their preparation and use
US4396623A (en) * 1981-08-26 1983-08-02 Southern Research Institute Carbocyclic analogs of uracil nucleosides as antiviral agents
US4415573A (en) * 1980-08-19 1983-11-15 Chugai Seiyaku Kabushiki Kaisha Novel uracil derivatives, process for preparing the same and a pharmaceutical composition containing the same
US4564618A (en) * 1982-09-17 1986-01-14 Glaxo Group Limited 5-Halovinyl-2'-deoxyuridine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415573A (en) * 1980-08-19 1983-11-15 Chugai Seiyaku Kabushiki Kaisha Novel uracil derivatives, process for preparing the same and a pharmaceutical composition containing the same
GB2084152A (en) * 1980-10-01 1982-04-07 Beecham Group Ltd Antiviral agents their preparation and use
US4396623A (en) * 1981-08-26 1983-08-02 Southern Research Institute Carbocyclic analogs of uracil nucleosides as antiviral agents
US4564618A (en) * 1982-09-17 1986-01-14 Glaxo Group Limited 5-Halovinyl-2'-deoxyuridine derivatives

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
C. Desgranges et al., ( Biochemical Pharmacology, vol. 32, pp. 3583 3590, 1983). *
C. Desgranges et al., (Biochemical Pharmacology, vol. 32, pp. 3583-3590, 1983).
Jasenka Matulic Adamic and Kyoichi A. Watanabe, J. Chem. Soc., Chem. Comm., 1985, pp. 1535 1536. *
Jasenka Matulic-Adamic and Kyoichi A. Watanabe, J. Chem. Soc., Chem. Comm., 1985, pp. 1535-1536.
Jerry March, "Advanced Organic Chemistry," 2nd Ed., McGraw-Hill Book Co., 1977, New York, N.Y.
Jerry March, Advanced Organic Chemistry, 2nd Ed., McGraw Hill Book Co., 1977, New York, N.Y. *
K. C. Murdock and R. B. Angier, Journal of the American Chemical Society, vol. 84, pp. 3758 3764. *
K. C. Murdock and R. B. Angier, Journal of the American Chemical Society, vol. 84, pp. 3758-3764.
Maggiora et al., Chemical Abstracts, vol. 104, (1986): 130206y. *
R. Kaul, K. Keppeler, G. Kiefer, B. Hempel, and P. Fischer, ( Chemosphere, vol. 11, pp. 539 540, 1982). *
R. Kaul, K. Keppeler, G. Kiefer, B. Hempel, and P. Fischer, (Chemosphere, vol. 11, pp. 539-540, 1982).
Shealy and Clayton, Journal of the American Chemical Society, vol. 88, pp. 3885 3887, 1966. *
Shealy and Clayton, Journal of the American Chemical Society, vol. 88, pp. 3885-3887, 1966.
Shealy et al., Chemical Abstract, vol. 104 (1986): 69111v. *
Shealy et al., Chemical Abstracts, vol. 104, (1986): 130207z. *
Shealy et al., Journal of Medicinal Chemistry, vol. 26, pp. 156 161 (1983). *
Shealy et al., Journal of Medicinal Chemistry, vol. 26, pp. 156-161 (1983).
Shealy, O Dell and Thorpe, Journal of Heterocyclic Chemistry, vol. 18, pp. 383 389 (1981). *
Shealy, O Dell, Thorpe and Coburn, Jr. Journal of Heterocyclic Chemistry, vol. 20, pp. 655 661 (1983). *
Shealy, O'Dell and Thorpe, Journal of Heterocyclic Chemistry, vol. 18, pp. 383-389 (1981).
Shealy, O'Dell, Thorpe and Coburn, Jr. Journal of Heterocyclic Chemistry, vol. 20, pp. 655-661 (1983).
Y. F. Shealy and C. A. O Dell, Journal of Heterocyclic Chemistry, vol. 13, pp. 1041 1047 (1976). *
Y. F. Shealy and C. A. O'Dell, Journal of Heterocyclic Chemistry, vol. 13, pp. 1041-1047 (1976).

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5496935A (en) * 1988-08-17 1996-03-05 Max-Delbru/ ck-Centrum 2',3'-dideoxynucleoside pyrimidine compounds and carbocyclic analogs
US5744600A (en) * 1988-11-14 1998-04-28 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Phosphonomethoxy carbocyclic nucleosides and nucleotides
WO1990009177A1 (en) * 1989-01-31 1990-08-23 Us Army Cyclopentenyl pyrimidines and methods of using same
WO1991015488A1 (en) * 1990-04-04 1991-10-17 Froud, Clive Carbo-nucleoside derivatives
US6177436B1 (en) 1990-07-19 2001-01-23 Glaxo Wellcome Inc. Pharmaceutical compositions of 5-alkynyl uracil compounds
EP0711555A3 (en) * 1990-07-19 1996-06-26 Wellcome Found
EP0711555A2 (en) * 1990-07-19 1996-05-15 The Wellcome Foundation Limited Enzyme inactivators
US6221852B1 (en) 1990-07-19 2001-04-24 Glaxo Wellcome Inc. Pharmaceutical compositions of 5-alkynyl-dideoxyribouracil
US6586440B2 (en) 1990-07-19 2003-07-01 Smithkline Beecham Corporation Pharmaceutical compositions of 5-alkynyl uracil compounds
US5817664A (en) * 1990-09-26 1998-10-06 Glaxo Wellcome Inc. Uracil reductase inactivators
WO1992004901A1 (en) * 1990-09-26 1992-04-02 The Wellcome Foundation Limited Uracil reductase inactivators
US6268374B1 (en) 1990-09-26 2001-07-31 Glaxo Wellcome Inc. Uracil reductase inactivators
US6297223B1 (en) 1990-09-26 2001-10-02 Glaxo Wellcome Inc. Uracil reductase inactivatores
US7119096B2 (en) 1990-09-26 2006-10-10 Smithklinebeecham Corporation Uracil reductase inactivators
US7704971B2 (en) 1990-09-26 2010-04-27 Smithklinebeecham Corporation Uracil reductase inactivators

Similar Documents

Publication Publication Date Title
Martin et al. Synthesis and antiviral activity of monofluoro and difluoro analogs of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1)
EP0307342B1 (en) 3-Demethyl-4-fluoro-mevalonic-acid derivatives, process for their preparation, pharmaceutical preparations based on those compounds, their use and intermediates
US5591722A (en) 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US4904770A (en) Production of 2',3'-dideoxy-2',3'-didehydronucleosides
US4177348A (en) Carbocyclic analogs of cytosine nucleosides
US5059690A (en) Purinyl tetrahydrofurans
Shealy et al. Carbocyclic analogs of thymine nucleosides and related 1‐substituted thymines
IE57071B1 (en) Improvements in or relating to novel difluoro antiviral agents
JPH026478A (en) Bis (hydroxymethyl)cyclobutylpurines and pyrimidines
JPH03141292A (en) Antiviral compound
CA2080916A1 (en) 2',3'-dideoxy-4'-thioribonucleosides as antiviral agents
US5314893A (en) Antiviral tetrahydropyrans
US4396623A (en) Carbocyclic analogs of uracil nucleosides as antiviral agents
US4719214A (en) Carbocyclic analogues of thymine nucleosides
Shealy et al. Synthesis and antiviral activity of the carbocyclic analogs of 5-ethyl-2'-deoxyuridine and of 5-ethynyl-2'-deoxyuridine
US5130421A (en) Production of 2',3'-dideoxy-2',3'-didehydronucleosides
US4232154A (en) Carbocyclic analogs of cytosine nucleosides exhibiting antiviral and antineoplasticactivity
US4728736A (en) Carbocyclic analogs of purine ribofuranosides
US3721664A (en) Preparation of 5-cytosine nucleosides
Shigeta et al. Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues
US4730001A (en) Carbocyclic analogues of amino and azido thymidines
Mitchell et al. Synthesis and antiviral properties of 5-(2-substituted vinyl)-6-aza-2'-deoxyuridines
CA1336516C (en) Acyl derivatives of 2-amino-4-substituted-5-hydroxy pyrimidines
US4895937A (en) 5-ioso-2-pyrimidinone nucleoside
EP0394893B1 (en) Purinyl and pyrimidinyl tetrahydrofurans

Legal Events

Date Code Title Description
AS Assignment

Owner name: SOUTHERN RESEARCH INSTITUTE, 2000 NINTH AVENUE SOU

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SHEALY, Y. FULMER;O'DELL, C. ALLEN;REEL/FRAME:004435/0947

Effective date: 19850722

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12